The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Tyrosine kinases (TKs) play a central role in cellular signaling networks, acting as relay points for multiple interdependent pathways that initiate from cell surface receptors and ultimately converge on gene expression within the nucleus. Delicate regulation of TK activity controls diverse cellular homeostatic mechanisms, such as the cell cycle, proliferation, differentiation, motility, and apoptosis or survival. TK activity is tightly regulated in normal cells but mutation(s), overexpression of TK, or aberrant autocrine activation may cause constitutive activation leading to malignancy. Consequently, TKs have emerged as clinically attractive target molecules for drug development.
Targeted TK inhibitors (TKIs) for cancer treatment represent a breakthrough in innovative intervention strategies. As TKIs become more widely used in clinical practice, it will be critical to identify subpopulations of patients who will respond to these therapies. However, the identification of potential TKI responders is not straightforward, as demonstrated by results of preclinical data with small molecule inhibitors, the complex nature of TK activation, and the lack of a standardized assay for measuring TK levels or activity in tumors.
Constitutive BCR-ABL1 TK activation and downstream signaling represent the pathogenetic hallmarks of chronic myelogenous leukemia (CML), and selective ABL1 TKI therapy has revolutionized the management of this disease. Three such selective TKIs are currently approved for treatment of CML and BCR-ABL1-positive (i.e., Philadelphia chromosome-positive) ALL: imatinib, nilotinib, and dasatinib. The clinical efficacy of imatinib, a selective ABL1 kinase inhibitor and the next generation more potent nilotinib, have been demonstrated in all phases of CML. However, the development of drug resistance constitutes a major drawback in the treatment of advanced-phase disease. Dasatinib, a highly potent dual inhibitor of ABL1 and Src, is recently approved by FDA for first-line therapy in CML patients who do not respond well to imatinib, even though dasatinib still has its own shortcoming and is not effective for certain subclass of resistant patients. Assays are needed to assist the physician in the appropriate diagnosis and selection of therapy for CML and ALL patients.